Background: Schizophrenia and schizoaffective disorder are treated with antipsychotic drugs. Some patients
show treatment-resistant forms of psychotic disorders and, in this case, they can be treated with clozapine. In these
patients and based on previous reviews on novel antipsychotic drugs, it is important to know whether an add-on therapy
with new drugs can ameliorate the positive and negative schizophrenic scale (PANSS) total score.
Objective: The aim of this review is to suggest an appropriate treatment for patients with treatment-resistant forms of
psychotic disorders. A combination of current available antipsychotic drugs with novel antipsychotic or modulating drugs
might improve negative schizophrenic symptoms and cognitive function and thereby social functioning and quality of life.
Results: The mechanisms of action, the therapeutic effects and the pharmacokinetic profiles of novel antipsychotic drugs
such as cariprazine, brexipiprazole and lumateperone are up-dated. Published case reports of patients with treatmentresistant psychoses are also discussed. These patients were treated with clozapine but a high PANSS total score was
observed. Only an add-on therapy with cariprazine improved the score and, above all, negative schizophrenic symptoms
and cognitive functions. To ensure a constant antipsychotic drug concentration, long-acting injectable antipsychotic drugs
may be a choice for a maintenance therapy in schizophrenia. New modulating drugs, such as receptor positive allosteric
modulators (N-methyl-D-aspartate receptor; subtype 5 of the metabotropic glutamatergic receptor) and encenicline, an
alpha7 nicotinic cholinergic receptor agonist, are being investigated in preclinical and clinical trials.
Conclusion: In clinical trials, patients with treatment-resistant forms of psychosis should be examined to know whether a
combination therapy with clozapine and a novel antipsychotic drug can ameliorate the PANSS total score. In
schizophrenia, long-acting injectable antipsychotic drugs are a safe and tolerable maintenance therapy. In further clinical
studies, it should be investigated whether patients with treatment-resistant forms of psychoses can improve negative
schizophrenic symptoms and cognitive functions by an add-on therapy with cognition enhancing drugs.